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Enantioselective process for cycloalkenyl ?-substituted alanines

a technology of cycloalkenyl ?substituted alanines and selective process, which is applied in the preparation of carbonyl compounds, organic chemistry, carboxylic acid amides, etc., can solve the problems of waste of about half of the quantity of precursor materials and produce undesired isomers, and achieves easy conversion and high yield

Active Publication Date: 2011-10-20
CHIRAL QUEST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]The present invention addresses the shortcomings of the prior art methodologies. The objective of this invention is to provide an alternative process for synthesizing cyclic amino acids that are useful intermediates of for Ramipril and Perindolpril. The present invention employs asymmetric hydrogenation to produce optically pure substituted alanines, which are easily converted to cyclic amino acids of interest. In contrast to the prior art chemical resolution processes, the presently claimed novel asymmetric hydrogenation procedure produces only one desired enantiomer with high yield. The presently claimed process is also advantageous from an economic and material utilization point of view.

Problems solved by technology

However, these processes waste about half of the quantity of the precursor material and produce undesired isomers.

Method used

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Examples

Experimental program
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Effect test

example 1

Preparation of 2-chloro-1-formyl-1-cyclopentene (VIA)

[0056]

[0057]To a three-necked flask fitted with a stirrer, thermometer, reflux condenser, additional funnel, nitrogen inlet, and calcium chloride drying tube were added dimethylformamide (71.8 g, 0.9 mol) and 1,2-dichloroethane (150 mL). The resulting mixture was stirred under nitrogen and cooled to 5° C. with an external ice bath. Phosphorus oxychloride was added during approximately 1 hour through an additional funnel while the temperature of the stirred reaction mixture being maintained below 10° C. The mixture was then allowed to warm to room temperature. A solution of cyclopentanone (55.5 g, 0.66 mol) in 1,2-dichloroethane (100 mL) was added at such a rate that the temperature did not rise above 35° C. When the addition was completed, the mixture was heated at 55-60° C. for 3 hours. The reaction mixture was then cooled to below 35° C., and a solution of sodium acetate (240 g) in water (560 mL) was cautiously added through an ...

example 2

Preparation of 2-phenoxy-1-formyl-1-cyclopentene (VIB)

[0059]

[0060]To a solution of residue (100 g, 0.77 mol) obtained in example 1 in acetone (400 mL), phenol (79.3 g, 0.84 mol) and K2CO3 (126.8 g, 0.92 mol) were added. The mixture was stirred under nitrogen for 12 hours at room temperature and monitored by TLC (petroleum ether / ethyl acetate=10:1). After the reaction completed, the solvent was removed on a rotary evaporator, and water (300 mL) was added. The mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with aqueous sodium carbonate (2×50 mL) and water (50 mL). After dried over sodium sulfate, the solvent was removed and 2-phenoxy-1-formyl-1-cyclopentene was obtained (155 g, contains some phenol), which was used directly in the next step.

example 3

Preparation of 4-((2-phenoxycyclopent-1-enyl)methylene-2-phenyloxzol-5(4H)-one (VIII)

[0061]

[0062]A mixture of 2-phenoxy-1-formyl-1-cyclopentene (150 g, obtained in example 2), acetic anhydride (196 g, 1.92 mol), sodium acetate (40 g, 0.48 mol) and benzoylglycine (125.7 g, 0.7 mol) was heated to 105-110° C. for about 1.5 h under nitrogen. The reaction was monitored by TLC (petroleum ether / ethyl acetate=15:1). After the reaction was completed, the mixture was cooled to 0° C., and then filtered. The cake was washed with methanol (2×150 mL) at room temperature. A brown to orange solid was obtained and dried in vacuum to afford 137 g product in 64.7% yield.

[0063]1H NMR (CDCl3, δ): 8.10-8.06 (m, 2H), 7.73-7.46 (m, 4H), 7.38-7.34 (m, 2H), 7.19-7.16 (m, 1H), 7.04-7.02 (m, 2H), 3.13 (t, 2H, J=7.2), 2.46 (t, 2H, J=7.6), 2.10-2.00 (m, 2H).

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Abstract

A process for preparing an enantiomerically enriched cycloalkene-substituted alanine compound having the structure:by asymmetrically hydrogenating a dehydro amino acid compound having the structure:in a suitable reaction media in the presence of a catalyst having a transition metal moiety complexed to a chiral phosphine ligand to prepare enantiomerically enriched cycloalkene substituted alanine compounds having the structure of Formula (IA) or (IB), which are key intermediates for the ACE inhibitors ramipril and perindolpril:

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 61 / 326,187 filed Apr. 20, 2010, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to an enantioselective process for preparing optically pure β-cycloalkenyl-substituted alanines (Formula I, IA and IB), which could be easily converted to cyclic amino acids (Formula II) that are key intermediates for the ACE inhibitors ramipril (Formula III) and perindolpril (Formula IV).[0003]Ramipril [A. Kleemann, J. Engel, Pharmaceutical Substances, 4th Edition, page 1785, Thieme Verlag Stuttgart, 2001] and perindolpril [EP 1565485, EP1688427] are ACE inhibitors which are frequently employed in the medical management of hypertension. One of the key intermediates is the cyclic amino acid of Formula II (n=1, 2). The five member ring amino acid with Formula II, wherein n is 1, is used for the preparation of Ramipril [WO...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C229/32C07D263/42C07C47/47C07C47/457C07C227/32C07D209/52
CPCC07C47/47C07C227/06C07D263/42C07D209/52C07C2101/10C07C233/86C07C231/18C07C231/12C07C231/10C07C229/28C07C2601/10
Inventor LIU, ZIJUNLIN, SANHUILI, WENGEZHU, JINGYANGLIU, XINJUNZHANG, XIAOJUANLU, HUIXIONG, FEITIAN, ZHONGWEI
Owner CHIRAL QUEST
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